Secretory autophagy-induced bladder tumour-derived extracellular vesicle secretion promotes angiogenesis by activating the TPX2-mediated phosphorylation of the AURKA-PI3K-AKT axis

Li, Xinyuan; Wei, Zongjie; Yu, Haitao; Xu, Yingjie; He, Weiyang; Zhou, Xiang; Gou, Xin

doi:10.1016/j.canlet.2021.09.036

Cited by 32 publications

(26 citation statements)

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“…Immunohistochemistry (IHC) analysis was performed as described previously [ 24 ]. IHC was performed using antibodies against CD31 (Cat# ab9498, Abcam, UK).…”

Section: Methodsmentioning

confidence: 99%

A novel risk score model based on five angiogenesis-related long non-coding RNAs for bladder urothelial carcinoma

Zhang

Peng

et al. 2022

Cancer Cell Int

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Background Tumour angiogenesis is an independent risk factor for bladder urothelial carcinoma (BUC) progression, but viable and promising antiangiogenic targets are understudied. Emerging evidence suggests that long non-coding RNAs (lncRNAs) play prominent role in the tumour microenvironment and tumour angiogenesis. Methods The clinical data of BUC patients were obtained from TCGA database and clinical specimens of 138 BUC patients. Univariate and multivariate COX regression analyses were used to identify survival-related ARLNRs (sARLNRs) from The Molecular Signatures Database v4.0. Fisher’s exact probability method was used to detect the correlations between sARLNRs levels and clinicopathological characteristics. A chain of experiments including FACS, qPCR, immunohistochemistry, tube formation, migration and invasion assays, combining with co-culture models, were utilized to validate the clinical significance and angiogenetic correlation of sARLNRs. Results Five sARLNRs were employed to establish an angiogenesis-related risk score model, by which patients in the low-risk group obtained better overall survival than those in the high-risk group. The expression of AC005625.1 and AC008760.1 was significantly related to ECs percentage, tumour size and muscle invasion status. Besides, AC005625.1 and AC008760.1 expressed lower in BUC cell lines and tumour tissues than that in normal urothelial cells and adjacent normal tissues, with much lower levels in more advanced T stages. A prominently higher proportion of ECs was detected in tumour tissues with lower expression of AC005625.1 and AC008760.1. In the co-culture models, we found that knockdown of AC005625.1 and AC008760.1 in BUC cells increased the tube formation, migration and invasion abilities of HUVEC. The expression levels of CD31, VEGF-A, VIMENTIN and N-CADHERIN were also enhanced in HUVEC cells co-cultured with siR-AC005625.1 and siR-AC008760.1-treated T24 cells. Conclusion In the study, we identify five sARLNRs and validate their clinical significance, angiogenesis correlation and prognosis-predictive values in BUC. These findings may provide a new perspective and some promising antiangiogenic targets for clinical diagnosis and treatment strategies of BUC.

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“…Immunohistochemistry (IHC) analysis was performed as described previously [ 24 ]. IHC was performed using antibodies against CD31 (Cat# ab9498, Abcam, UK).…”

Section: Methodsmentioning

confidence: 99%

A novel risk score model based on five angiogenesis-related long non-coding RNAs for bladder urothelial carcinoma

Zhang

Peng

et al. 2022

Cancer Cell Int

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“…GFAT1, as a type of NSP, has been reported to be secreted via exosomes, [ 30 ] consistent with our previous finding that secretory autophagy promoted sEV‐mediated NSP secretion in the TME. [ 31 ] Therefore, we isolated sEVs from the medium of normal urothelial cells (sEVs NC ) and BCa cells (sEVs Tu ) ( Figure 2 A–C ), and examined the protein profiles of sEVs NC and sEVs Tu using 4D‐label‐free LC–MS/MS (Figure S2A , Supporting Information). As expected, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested that the upregulated proteins in the sEVs Tu were mainly enriched for the metabolic process and O‐glycan biosynthesis pathway (Figure 2D and Figure S2B , Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

“…Immunoblotting analysis was performed as described previously. [ 31 ] SDS–PAGE gels and PVDF membranes (Millipore, MA, USA) were used for protein separation and blotting, respectively. The protein bands were visualized with enhanced chemiluminescence (Bio–Rad, USA) and quantified using ImageJ software (NIH, USA).…”

Section: Methodsmentioning

confidence: 99%

“…[ 30 ] Our previous study demonstrated that the strengthened secretory autophagy observed in a nutrient‐deprived environment promotes NSP secretion via LC3‐conjugated small extracellular vesicles. [ 31 ] We, therefore, speculate that BCa‐derived GFAT1, through intercellular communication in the TME, mediates HBP‐related metabolic reprogramming and functional regulation in ECs.…”

Section: Introductionmentioning

confidence: 99%

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Bladder Cancer‐Derived Small Extracellular Vesicles Promote Tumor Angiogenesis by Inducing HBP‐Related Metabolic Reprogramming and SerRS O‐GlcNAcylation in Endothelial Cells

Peng

Zhang

et al. 2022

Advanced Science

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A malformed tumour vascular network provokes the nutrient-deprived tumour microenvironment (TME), which conversely activates endothelial cell (EC) functions and stimulates neovascularization. Emerging evidence suggests that the flexible metabolic adaptability of tumour cells helps to establish a metabolic symbiosis among various cell subpopulations in the fluctuating TME. In this study, the authors propose a novel metabolic link between bladder cancer (BCa) cells and ECs in the nutrient-scarce TME, in which BCa-secreted glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1) via small extracellular vesicles (sEVs) reprograms glucose metabolism by increasing hexosamine biosynthesis pathway flux in ECs and thus enhances O-GlcNAcylation. Moreover, seryl-tRNA synthetase (SerRS) O-GlcNAcylation at serine 101 in ECs promotes its degradation by ubiquitination and impeded importin 𝜶5-mediated nuclear translocation. Intranuclear SerRS attenuates vascular endothelial growth factor transcription by competitively binding to the GC-rich region of the proximal promotor. Additionally, GFAT1 knockout in tumour cells blocks SerRS O-GlcNAcylation in ECs and attenuates angiogenesis both in vitro and in vivo. However, administration of GFAT1-overexpressing BCa cells-derived sEVs increase the angiogenetic activity in the ECs of GFAT1-knockout mice. In summary, this study suggests that inhibiting sEV-mediated GFAT1 secretion from BCa cells and targeting SerRS O-GlcNAcylation in ECs may serve as novel strategies for BCa antiangiogenetic therapy.

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“…TPX2 was found in in silico studies to be related to the risk of the distant metastasis of breast cancers [44]. In bladder cancer, TPX2 is involved in TPX2-mediated phosphorylation of the AURKA-PI3K-AKT axis [45]. In addition, heterogeneous nuclear ribonucleoprotein F, by regulating the TPX2 protein, promotes the cell cycle and proliferation of bladder cancer cells [46].…”

Section: Discussionmentioning

confidence: 99%

Computational Analysis Identifies Novel Biomarkers for High-Risk Bladder Cancer Patients

Piliszek

Brożyna

Rudnicki

2022

IJMS

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In the case of bladder cancer, carcinoma in situ (CIS) is known to have poor diagnosis. However, there are not enough studies that examine the biomarkers relevant to CIS development. Omics experiments generate data with tens of thousands of descriptive variables, e.g., gene expression levels. Often, many of these descriptive variables are identified as somehow relevant, resulting in hundreds or thousands of relevant variables for building models or for further data analysis. We analyze one such dataset describing patients with bladder cancer, mostly non-muscle-invasive (NMIBC), and propose a novel approach to feature selection. This approach returns high-quality features for prediction and yet allows interpretability as well as a certain level of insight into the analyzed data. As a result, we obtain a small set of seven of the most-useful biomarkers for diagnostics. They can also be used to build tests that avoid the costly and time-consuming existing methods. We summarize the current biological knowledge of the chosen biomarkers and contrast it with our findings.

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Secretory autophagy-induced bladder tumour-derived extracellular vesicle secretion promotes angiogenesis by activating the TPX2-mediated phosphorylation of the AURKA-PI3K-AKT axis

Cited by 32 publications

References 58 publications

A novel risk score model based on five angiogenesis-related long non-coding RNAs for bladder urothelial carcinoma

A novel risk score model based on five angiogenesis-related long non-coding RNAs for bladder urothelial carcinoma

Bladder Cancer‐Derived Small Extracellular Vesicles Promote Tumor Angiogenesis by Inducing HBP‐Related Metabolic Reprogramming and SerRS O‐GlcNAcylation in Endothelial Cells

Computational Analysis Identifies Novel Biomarkers for High-Risk Bladder Cancer Patients

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